MECHANISM-BASED EVOLUTION OF NOVEL CATALYTIC ANTIBODIES

新型催化抗体的基于机制的进化

• 批准号: 5207077
• 负责人: RICHARD A LERNER
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5207077
• 关键词: Diels Alder reaction; X ray crystallography; abzyme; chemical elimination; chemical kinetics; chemical reaction; chemical synthesis; haptens; nuclear magnetic resonance spectroscopy

Following the discoveries of catalytic activity in antibodies raised to transition state analogs, it has become clear that antibodies can catalyze a wide range of chemical reactions that are catalyzed in nature by enzymes. Recent work has focused on chemical reactions that do not occur in natural systems, such as Diels-Alder reactions, which, however, can occur chemically. Catalytic antibodies have the advantage that they can also catalyze reactions that are chemically disfavored due to steric hindrance. It is proposed to study antibody catalysis of disfavored reactions, beginning with the dissection of the catalysis of a highly disfavored syn elimination reaction to form a cis olefin. The second major aim is to elicit antibodies of improved function by utilizing mechanism-based induction. We will be utilizing considerable expertise and experience in the laboratory in hapten design and antibody production and characterization. It is anticipated that fruitful collaborations with the other three projects will follow the beginnings outlined in this proposal, and that structural work will commence shortly using both X-ray crystallography and NMR on several of the catalytic antibodies produced as part of this project. This work will lead to a better understanding of the structural basis of antibody catalysis, and it will give valuable insights into the nature of catalysis in solution in general.

在发现抗体的催化活性后， 过渡态类似物，很明显抗体可以催化 一系列的化学反应，在自然界中被催化， 内切酶 最近的工作集中在不发生的化学反应上 在自然系统中，例如Diels-Alder反应，然而， 化学发生。 催化抗体的优势在于， 也催化由于空间位阻而在化学上不利的反应， 阻碍。 建议研究抗体催化不利的 反应，开始解剖的催化作用的高度 不利的顺式消除反应以形成顺式烯烃。 第二 主要目的是通过利用抗体来引发功能改善的抗体。 基于机制的归纳 我们将利用大量的专业知识 在半抗原设计和抗体生产方面的实验室经验 和特征化。 预计，与 其他三个项目将遵循本报告概述的开端， 建议，结构工作将很快开始使用X射线 晶体学和核磁共振对几种催化抗体产生的， 这个项目的一部分。 这项工作将有助于更好地了解 抗体催化的结构基础，它将提供有价值的 对溶液中催化作用本质的一般认识。